Metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. There is evidence that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors. (Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990). Tumor necrosis factor (TNF) is a cell associated cytokine which has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. There is considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) non-insulin dependent diabetes melitus, (Lohmander L .S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301). PCT International Publication No. WO97/18207 discloses novel macrocycles of formula (I) which act as inhibitors of MMPs, in particular aggrecanase and TNF-C, thereby preventing cartilage loss by inflammatory disorders involving TNF. ##STR2##
Among the most synthetically challenging are the macrocyclic analogs containing a succinate residue in which the 5(R), 6(S) stereochemistry is desired: ##STR3##
The previous synthesis of the 2,3-disubstituted succinate is described in Scheme 1. An acid halide is converted to its oxazolidinone derivative and the auxiliary directs the subsequent alkylation with t-butyl bromoacetate to afford the 5(R) stereocenter. The oxazolidinone group is removed using H.sub.2 O.sub.2 /LiOH. Treatment of the enolate of this acid intermediate with a triflate derivative of a di-alcohol protected at one terminus as the benzyl ether produces a succinate derivate. This intermediate, however, requires epimerization because the alkylation consistently favors the undesired syn product. In order to separate the epimerization products, the acid is esterified and subject to chromatography. Following separation, the acid is hydrolyzed and coupled with a variety of amino acids such as tyrosine or lysine which contain .alpha.-side chains amenable to cyclization. The benzyl group is removed by hydrogenation and the resulting alcohol converted to a bromide using carbon tetrabromide and triphenyl phosphine. Macrocyclization of the tyrosine or lysine derivative is accomplished using potassium carbonate in N,N-dimethylformamide. Cyclization of the lysine derivative may also be accomplished with phosgene, leading to a carbamate bridge in the macrocycle. The t-butyl group is deprotected using TFA to give the carboxylic acid, and if desired, the acid is converted to a hydroxamic acid by coupling with hydroxylamine. ##STR4##
The present invention describes a new and useful process for the preparation of these macrocycles, which employs a highly stereoselective Ireland-Claisen rearrangement to form the anti-succinate residue: ##STR5##
Generally, the production of anti-adducts requires either an E olefin and a Z enolate-E silyl ketene acetal or a Z olefin and an E enolate-Z silyl ketene acetal (J. Am. Chem. Soc. 1976, 98, 2868). The Claisen precursor of the present invention can be obtained by reacting an O-protected lithium 4-pentyn-1-ol (or a 4-halopentyne derivative) with an acyl chloride to give a propargylic ketone. Asymmetric reduction of the carbonyl with S-Alpine Borane.RTM. followed by hydride reduction of the alkyne yields the desired E-allylic alcohol. Acylation of the alcohol gives the scalemic ester used in the rearrangement.
The Claisen rearrangement proceeds with exceptional diastereoselectivity under the preferred conditions, eliminating the need for chromatography. The silyl ester product of the rearrangement can be isolated or immediately hydrolyzed with hydroxide to give the free acid which is then available for coupling with various .alpha.-amino acids. The compound which results from the subsequent manipulation of the chain terminus serves as the macrocyclization precursor.
If a derivative of tyrosine is used as the amino acid, the ring may be cyclized under basic conditions. This cyclization proceeds under the preferred conditions through the use of cesium carbonate in dimethyl sulfoxide and N,N-dimethylformamide. In similiar fashion, if the amino acid is a .omega.-protected lysine derivative, macrocyclization can be accomplished by reacting an acyclic alcohol and the deprotected amine with phosgene or an equivalent thereof in the presence of an acid scaventger to give a carbamate linkage.
Compounds of formula (IX) or (IX-a) result when amino acids derivatives such as tyrosine or lysine are coupled with the anti-succinate residues formed by a Claien rearrangement, and subsequently cyclized. ##STR6##
These macrocycles are converted to the corresponding carboxylic acids with KMnO.sub.4 in the presence of NaIO.sub.4, or with ozone. If desired, the resultant acids can be converted to alternative chelators such as hydroxamic acids by activation of the carbonyl and subsequent treatment with hydroxylamine.
Production of the anti-succinate residue (Ib) poses significant synthetic challenges to large scale drug preparation. In order to prepare large quantities of the desired therapeutic agents, an economically viable preparation of the anti-succinate, which is practical for scale-up, is necessary. The present invention obviates the need for epimerization and tedious purification protocols. As a result, the production of these important compounds is more efficient and cost effective.